Strategies for Patients with Relapsed/Refractory Multiple Myeloma

CASE SUMMARY

A 63-year-old man, who was diagnosed 8 years ago with IgG-κ multiple myeloma, presented with penta-refractory disease progression after 4 prior lines of therapy, including autologous stem cell transplant, 2 proteasome inhibitors (PIs), 2 immunomodulatory drugs (IMiDs), and 1 anti-CD38 antibody. His personal medical history included hypertension controlled with lisinopril and he had ECOG performance score of 1. The patient asked about CAR (chimeric antigen receptor) T-cell therapy, but after counseling, opted to pursue an alternative therapeutic due to waiting lists at accessible institutions.

Targeted Oncology^TM: What stands out to you in a patient case like this?

HILLENGASS: We have a patient in the early stages with smoldering myeloma. Most times, we don't know that but if we know then we can follow them. Then, at some point, patients will develop symptoms and they progress, [which is when] we start treatment. Most of the patients go right into remission with induction treatment, and then potentially stem cell transplant, then maintenance treatment.

But at some point, hopefully many years later, the relapse occurs [so we will] treat them again.Oftentimes, it's more difficult to bring them in to a remission or a similarly deep remission. Still, we have good options in the second-line, and then when the relapse comes again the patients will go into the next line of treatment and so on. [When] they are relapsed and refractory, based on the National Comprehensive Cancer Network [NCCN] guidelines, we have the whole list [of treatments], or the patients have toxicity and nothing is available anymore, then the patients, unfortunately, most of the time pass away from the disease.¹

What therapies play a role in treating a patient with multiple myeloma?

We have the IMiDS, lenalidomide [Revlimid] and pomalidomide [Pomalyst]. I don't mention thalidomide [Thalomid] too often in the United States, but in Germany, we still use it. Since I've in the Unites States, we’ve barely use thalidomide. Then, the PIs include bortezomib [Velcade], carfilzomib, and rarely we use ixazomib. Then of course [there is the] monoclonal antibodies, and those are our big drug classes, including daratumumab [Darzalex], elotuzumab [Empliciti], and isatuximab [Sarclisa]. Those are what we use in different combinations.

In most patients now, we give quadruplet treatments like daratumumab, lenalidomide, dexamethasone, and bortezomib. If the patients become refractory to that, then we already have some of our good drugs out of the way, but the good thing is that we usually have long progression-free survivals in those patients [on the quadruplet regimen], and even with a transplant, it can be longer. Some patients, if they're high-risk, even get a doublet maintenance therapy.

[When we] come to the point that we give the next line of treatment, what I usually do is I try to switch out as many drug classes as possible. If the patient progresses on lenalidomide maintenance, for example, I switch to a PI and/or an antibody. Then, if we give that and the disease comes back, we are in third line [of treatment].

After the third line, I have to admit that it starts to become challenging [to treat]. Then, I go back to things like bendamustine or cyclophosphamide, the stuff that I used when I was a resident. Despite all these new developments, there was still, or is still, a need to develop new drugs and new treatment approaches [in the third-line setting].

What targets are most prevalent in multiple myeloma care?

The b-cell maturation antigen [BCMA] is kind of the target that's new and shiny, and we are excited to have access to it. It is on the surface of nearly all myeloma cell lines, also most patients’ myeloma samples, and it's more on the malignant plasma cells than on healthy plasma cells, which is relevant.2 Unfortunately, it's also on healthy plasma cells, which is one of the reasons why a lot of the adverse events [AEs] that we see in the patients who are being treated with these BCMA-directed treatments are related to that, as the patients lose the healthy plasma cells as well.

The BCMA level is, as many other targets that we use in oncology in general, oftentimes also a negative prognostic marker. So, high BCMA levels are bad prognostic markers for [patients with multiple] myeloma. The up regulation of the expression is going up from normal, as compared with monoclonal gammopathy of undetermined significance to smoldering to multiple myeloma, and then to relapsed/refractory myeloma. So, there's more BCMA expression, which then correlates with the worse prognosis.

The NCCN guidelines now show or suggest treatment with BCMA-directed treatments. One of the drugs that we have used in the past was belantamab mafodotin [Blenrep], the BCMA-directed antibody drug conjugate, which has been taken off the market….³ Now, there are 2 CAR T-cell products, idecabtagene vicleucel [Abecma] and ciltacabtagene autoleucel [Carvyti], and newly approved teclistamab [Tecvayli] available in the guidelines and recommended for treatment of patients who had more than 3 prior lines of therapy.⁴

I mentioned the antibody-drug conjugate [as well]. The concept there is the antibody directed against a target in the myeloma cells, and in this case, BCMA is connected with a very toxic payload and the concept of the mechanism of action is that these antibodies are injected basically by the cancer cell, by the myeloma cell, and that leads to cell death, and it's very specific. There are some AEs that were new to us, like ocular toxicity, but this is basically the concept of how the antibody-drug conjugates that we also know from other cancers are working.

What is the role of CAR T-cell therapy for treating a patient like this?

We collect T cells, take them out of the patient, and at the moment, we send them to a company who puts in a gene so that the T cells express an antigen receptor, the CAR. That is then when the patient gets the T cells back, which attach to the myeloma cells and kill the myeloma cells. [It is a] very effective treatment.

Then, instead of taking the T cells out of the patient, we leave the T cells where they are in the patient already, but we give a bispecific antibody, and there are different names for that and different structures. But the concept is that we attach to myeloma cell and, on the other side of the antibody, we attach the T cell or an natural killer cell, and we bring those cells together. The effect of the cytotoxic immune cell is that also the cancer cell is being killed, so those are the concepts that we have, and all of those are mostly available directly against BCMA.

^References:

^{1. National Comprehensive Cancer Network Guidelines. Multiple myeloma; Version 3.2023. Accessed April 14, 2023. https://bit.ly/3KYDaWf}

^{2. Yu B, Jiang T, Liu D. BCMA-targeted immunotherapy for multiple myeloma. J Hematol Oncol. 2020 Sep 17;13(1):125. doi:10.1186/s13045-020-00962-7}

^{3. Withdrawal of Blenrep from the US Market. International Myeloma Foundation. November 23, 2022. Accessed April 14, 2023. https://bit.ly/41v4CS0}

^{4. FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma. FDA. October 25, 2022. Accessed April 14, 2023. https://bit.ly/41z5qFv}